Autocrine production of interleukin-4 and interleukin-10 is required for survival and growth of thyroid cancer cells

Ruggero De Maria Marchiano, Matilde Todaro, Monica Zerilli, Lucia Ricci-Vitiani, Miriam Bini, Mileidys Perez Alea, Ada Maria Florena, Laura Miceli, Gerolama Condorelli, Sebastiano Bonventre, Giuseppe Di Gesù, Giorgio Stassi

Risultato della ricerca: Contributo in rivistaArticolo in rivista

94 Citazioni (Scopus)

Abstract

Although CD95 and its ligand are expressed in thyroid cancer, the tumor cell mass does not seem to be affected by such expression. We have recently shown that thyroid carcinomas produce interleukin (IL)-4 and IL-10, which promote resistance to chemotherapy through the up-regulation of Bcl-xL. Here, we show that freshly purified thyroid cancer cells were completely refractory to CD95-induced apoptosis despite the consistent expression of Fas-associated death domain and caspase-8. The analysis of potential molecules able to prevent caspase-8 activation in thyroid cancer cells revealed a remarkable up-regulation of cellular FLIPL (cFLIPL) and PED/PEA-15, two antiapoptotic proteins whose exogenous expression in normal thyrocytes inhibited the death-inducing signaling complex of CD95. Additionally, small interfering RNA FLIP and PED antisense sensitized thyroid cancer cells to CD95-mediated apoptosis. Exposure of normal thyrocytes to IL-4 and IL-10 potently up-regulated cFLIP and PED/PEA-15, suggesting that these cytokines are responsible for thyroid cancer cell resistance to CD95 stimulation. Moreover, treatment with neutralizing antibodies against IL-4 and IL-10 or exogenous expression of suppressor of cytokine signaling-1 of thyroid cancer cells resulted in cFLIP and PED/PEA-15 down-regulation and CD95 sensitization. More importantly, prolonged IL-4 and IL-10 neutralization induced cancer cell growth inhibition and apoptosis, which were prevented by blocking antibodies against CD95 ligand. Altogether, autocrine production of IL-4 and IL-10 neutralizes CD95-generated signals and allows survival and growth of thyroid cancer cells. Thus, IL-4 and IL-10 may represent key targets for the treatment of thyroid cancer. ©2006 American Association for Cancer Research.
Lingua originaleEnglish
pagine (da-a)1491-1499
Numero di pagine9
RivistaCancer Research
Volume66
DOI
Stato di pubblicazionePubblicato - 2006

Keywords

  • Aged
  • Antibodies
  • Apoptosis
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Cancer Research
  • Cell Growth Processes
  • Cell Line, Tumor
  • Humans
  • Interleukin-10
  • Interleukin-4
  • Intracellular Signaling Peptides and Proteins
  • Janus Kinase 1
  • Middle Aged
  • Oligonucleotides, Antisense
  • Oncology
  • Phosphoproteins
  • Protein-Tyrosine Kinases
  • Repressor Proteins
  • STAT6 Transcription Factor
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Thyroid Neoplasms
  • Up-Regulation
  • fas Receptor

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